Smoking is the largest preventable cause of death and disease in the United States, with about 46 million U.S. Adults currently smoking (CDC, 2007). Though there are medications approved by the FDA to treat nicotine addiction, a clinical study evaluating two of these drugs, varenicline and bupropion, showed that at least 80% of the treatment group participants relapsed within one year (Gonzales, et al., 2006). Interestingly, failed smoking cessation has been shown to have genetic contributions (Xian et al., 2003~ Broms et al., 2006~ Lessov et al., 2004). Though development of novel compounds may yield more promising drugs, a new strategy tailoring pharmacotherapies to genetic information is the next frontier in the treatment of nicotine addiction (Ho et al., 2010). However, though there are genome-wide association studies demonstrating a genetic contribution in nicotine addiction, there are no published studies addressing th mechanism of pharmacogenetics in treating nicotine dependence. One protein associated with mechanisms of both gene regulation and nicotine response is the transcription factor CREB. Experiments outlined in this proposal aim to investigate the role of CREB and associated genomic mechanisms in the potential therapeutic application of two nicotinic compounds for treatment of nicotine addiction, and elucidate possible mechanisms of action using cutting-edge molecular, functional, and behavioral techniques. My research so far in the nicotinic field has given me a solid foundation in basic science approaches, including biochemistry, pharmacology, and animal behavior. However, the specialized training proposed in genomics and functional imaging during the K99 phase of this award will broaden my knowledge base and increase the translational impact of my research. Furthermore, this training and individualized research project will serve me well during job searches for an academic tenure-track position.